Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs)

Yuan, Xue; Chen, Yong; Tang, Minghai; Wei, Yuhan; Shi, Mingsong; Yang, Yingxue; Zhou, Yanting; Liu, Jiang; Liu, Kongjun; Deng, Dexin; Zhang, Chufeng; Chen, Lijuan

doi:10.1021/acs.jmedchem.2c00604

Cited by 16 publications

(9 citation statements)

References 34 publications

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“…In our previous studies on the screening of RIPK2 inhibitors, we occasionally found that compound L1 could induce potent and rapid vacuolization in the rat cardiomyocyte cell line H9C2 when RIPK2 inhibitors were evaluated for cell toxicity in our recent research. 26 Moreover, compound L1 could completely induce vacuolization phenotype in human cervical adenocarcinoma cell line HeLa and human triple-negative breast cancer cell line MDA-MB-231 cells at 1 μM. This unexpected finding has aroused our great interest to explore the mechanism and further structural modifications based on L1, with MOMIPP, D-13, and apilimod as positive 1.…”

Section: ■ Biological Results and Discussionmentioning

confidence: 97%

“…The synthesis route of intermediate 1 has been reported previously. 26 The corresponding compounds L1 and L6−23…”

Section: ■ Chemistrymentioning

confidence: 99%

“…The general procedure for synthesizing the target molecules L1–23 has been outlined in Schemes and . The synthesis route of intermediate 1 has been reported previously . The corresponding compounds L1 and L6–23 were obtained from intermediate 1 through the Suzuki reaction with the respective boronic acid derivatives.…”

Section: Chemistrymentioning

confidence: 99%

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Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers

Chen,

Liu,

Wei

et al. 2023

J. Med. Chem.

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Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound L22 exhibited a remarkable interaction with PIKfyve kinase, boasting a K d value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound L22 is unequivocally attributed to methuosis as it differs from apoptosis, necrosis, or autophagy. Importantly, when administered orally, L22 effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of L22 as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.

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Section: ■ Biological Results and Discussionmentioning

confidence: 97%

“…The synthesis route of intermediate 1 has been reported previously. 26 The corresponding compounds L1 and L6−23…”

Section: ■ Chemistrymentioning

confidence: 99%

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Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers

Chen,

Liu,

Wei

et al. 2023

J. Med. Chem.

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“…Yuan et al designed a new series of RIPK2 pyrrolopyrimidine inhibitors based on structural modification of the FLT3 inhibitor CHMFL-FLT3-165 ( Figure 12 ) ( Wu et al, 2016 ; Yuan et al, 2022 ). CHMFL-FLT3-165 strongly inhibited RIPK2 and RIPK5 at 1 μM concentration.…”

Section: Ripk2 Inhibitorsmentioning

confidence: 99%

Recent advances in the development of RIPK2 modulators for the treatment of inflammatory diseases

2023

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Receptor-interacting serine/threonine kinase 2 (RIPK2) is a vital immunomodulator that plays critical roles in nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs) signaling. Stimulated NOD1 and NOD2 interact with RIPK2 and lead to the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK), followed by the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23. Defects in NOD/RIPK2 signaling are associated with numerous inflammatory diseases, including asthma, sarcoidosis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), multiple sclerosis, and Blau syndrome. As RIPK2 is a crucial element of innate immunity, small molecules regulating RIPK2 functions are attractive to establish novel immunotherapies. The increased interest in developing RIPK2 inhibitors has led to the clinical investigations of novel drug candidates. In this review, we attempt to summarize recent advances in the development of RIPK2 inhibitors and degraders.

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“…These compounds were used as the chemical probes to investigate the RIPK2 kinase and NOD signalling functions. Although these compounds bear potent inhibition and good selectivity, moderate PK properties limited their further development to enter into clinical study, and more research was going on 17–21 . Notably, GSK2983559 22 , a prodrug of compound P5 23 , has good kinase specificity and excellent activity in vivo.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

Fan

Chen

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro , compound 14 exhibited high affinity (IC 50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.

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Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs)

Cited by 16 publications

References 34 publications

Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers

Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers

Recent advances in the development of RIPK2 modulators for the treatment of inflammatory diseases

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

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